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Los Angeles, CA: It’s staggering to think that for every single cell in our body, there is another microbial cell, with its own genes, functions, and phenotypes, inhabiting our body and influencing our biology. From birth, our gut, mouth, skin, lungs, urogenital tract, and so forth are colonized by microbes that change over time but remain with us throughout our lives. Recent data suggests there are 30-50 trillion microbes present in the human microbiome, compared with ~30 trillion human cells1. While the absolute number of cells may be comparable, the amount of genetic content is not, with typically 750,000 non-redundant genes in the gut microbiome of an individual, relative to the ~20,000 genes in the human genome3.
It’s understood that microbes residing in our system have a role in a number of processes such as 1) nutrition, by breaking down foods that we cannot digest and helping the body absorb nutrients that might otherwise be lost; and 2) immunity, by generating compounds to reduce inflammation or prevent growth of harmful microbes. The importance of the microbiome has been recognized by experts in the field for some time. In a 2001 commentary on completion of the human genome (draft release – 90% coverage), microbiologist Julian Davies wrote, “Until the synergistic activities between humans and commensal microbiota has been elucidated, an understanding of human biology will remain incomplete.”2
The contribution of the human microbiome to health and disease is emerging with the aid of initiatives like The NIH Human Microbiome Project (2008), along with technological advances in high throughput sequencing, proteomics, metabolomics and computational analysis tools, which together are enabling researchers to fully characterize the microbiome. Studies have implicated the microbiome in a host of diseases including irritable bowel syndrome, inflammatory bowel disease, cardiovascular disease, and rheumatoid arthritis, among others. A recent study published in Cell implicates gut microbiota in the regulation of motor deficits and neuroinflammation in a mouse model of Parkinson’s disease. In 2013, Kang and colleagues found reduced incidence of a specific bacterium in the intestinal microflora of autistic children. Several other groups are pursuing the role of the microbiome in neurological disorders. Evidence continues to build and microbiome papers are being published at an almost exponential rate (~2,300 in 2016).
To characterize the research field, we used Network Analysis Interface for Literature Studies4 (NAILS) to analyze ~7,500 microbiome papers published since 2010. Below are the top researchers by publications and citations. Scroll over each circle for publication and citation count.
Important papers were identified and ranked using NAILS, which uses the following criteria:
|Huttenhower C||Human Microbiome Project Consortium||Structure, function and diversity of the healthy human microbiome.||2012||PubMed|
|Qin J||BGI-Shenzhen||A human gut microbial gene catalogue established by metagenomic sequencing||2010||PubMed|
|Arumugam M||European Molecular Biology Laboratory||Enterotypes of the human gut microbiome||2011||PubMed|
|Yatsunenko T||Washington University School of Medicine||Human gut microbiome viewed across age and geography||2012||PubMed|
|Wu GD||University of Pennsylvania||Linking long-term dietary patterns with gut microbial enterotypes||2011||PubMed|
|Dominguez-Bello MG||University of Puerto Rico||Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns||2010||PubMed|
|De Filippo C||University of Florence||Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa||2010||PubMed|
|David LA||Harvard University||Diet rapidly and reproducibly alters the human gut microbiome||2014||PubMed|
|Koenig JE||Cornell University||Succession of microbial consortia in the developing infant gut microbiome||2011||PubMed|
|Methé BA||Human Microbiome Project Consortium||A framework for human microbiome research||2012||PubMed|
|Qin J||BGI-Shenzhen||A metagenome-wide association study of gut microbiota in type 2 diabetes||2012||PubMed|
|Ravel J||University of Maryland School of Medicine||Vaginal microbiome of reproductive-age women||2011||PubMed|
|Le Chatelier E||Institut National de la Recherche Agronomique||Richness of human gut microbiome correlates with metabolic markers||2013||PubMed|
|Cho I||NYU Langone Medical Center||The human microbiome: at the interface of health and disease||2012||PubMed|
|Dewhirst FE||The Forsyth Institute||The human oral microbiome||2010||PubMed|
Although the exact impact of the microbiome on health and diseases is still undetermined and is in many cases complicated and unclear, several large biopharma players are making early bets. Microbiome-focused companies and start-ups have brought in over $600M in investments to further understand, and to develop drugs and compounds that target the microbiome. In January 2015, Vedanta entered into a licensing agreement with Janssen Biotech Inc. worth up to $339M in upfront and milestone payments to advance a lead drug candidate for IBD. In June 2016, Vedanta closed an additional $50M in financing. In April 2016, Second Genome raised $42.6M in financing led by the venture divisions of Pfizer and Roche, followed by an additional $8.4M from GlaxoSmithKline’s venture unit in July. Second Genome’s lead candidate, SGM-1019, is a small molecule inhibitor of a microbiome-mediated target involved in inflammation and pain in IBD patients. These significant investments are not going unnoticed and have catapulted the microbiome into the mainstream media spotlight.
The effects of the microbiome and potential applications appear to be far reaching, one of the key reasons for the excitement in this field. Current clinical trials are investigating the microbiome in a wide range of conditions including asthma, atopic dermatitis, cancer, cystic fibrosis, depression, diabetes, HIV, and multiple sclerosis. The microbiome is also crossing paths with the hottest area in biopharma—immuno-oncology. Last month Bristol-Myers Squibb, the makers of Opdivo which has brought in ~$2.5B in revenue in 2016, announced an immuno-oncology collaboration with Enterome Bioscience focused on microbiome-based biomarkers, drug targets and bioactive molecules. In August, Vedanta Biosciences announced a collaboration with NYU Langone Medical Center to develop microbiome-derived immunotherapies.
While most microbiome companies are focused on therapeutics, diagnostic players are also joining the party. Oslo-based Genetic Analysis has a CE-marked test for detecting bacterial imbalance in IBS and IBD patients called GA-map. Genetic Analysis recently entered into a partnership with Bio-Rad, who will receive an equity stake in exchange for commercialization rights. Second Genome partnered with AbbVie to create a molecular diagnostic for Crohn’s disease alongside its other therapeutics.
While the promise of the microbiome is great, the challenge of creating therapeutics to target the microbiome is significant. In July, Seres Therapeutics’ drug SER-109, designed to treat recurring infections of Clostridium difficile, failed to reach its primary efficacy endpoint in a phase II study, causing its stock to plummet from $35 to below $10 per share. In a therapeutic field as dynamic as the microbiome itself, we can expect to see constant change in the market landscape, the players, and the potential therapeutic applications.
Disclaimer: Companies listed above may be DeciBio clients and/or customers
Miguel Edwards, Senior Associate at DeciBio Consulting; [email protected]
Anthony DeBenedetti, Associate at DeciBio Consulting; [email protected]
Christopher Lew, Analyst at DeciBio Consulting; [email protected]
1 Sender R., Fuchs S., Milo R., Revised Estimates for the Number of Human and Bacteria Cells in the Body. PLOS Biology 2016
2 Davies J., In a Map for Human Life, Count the Microbes, Too. Science 2001
3 The gut microbiome in health and in disease. Current Opinion Gastroenterology. 2015
4 Knutas, A., Hajikhani, A., Salminen, J., Ikonen, J., Porras, J., 2015. Cloud-Based Bibliometric Analysis Service for Systematic Mapping Studies. CompSysTech 2015